ABSTRACT Traumatic brain injury (TBI) affects millions of people worldwide every year and current estimates from the World Health Organization suggest that TBI will be the third leading cause of death and disability by the year 2020. Despite being a prevalent and pressing global medical issue, our understanding of TBI pathoetiology remains incomplete. Proper drainage of cellular debris by the lymphatic system is required to maintain tissue homeostasis and impaired removal of damage/stress signals, including damaged cells and protein aggregates, from organs has been linked to a spectrum of diseases. In comparison to other peripheral organs, our understanding of how our how defects in lymphatic drainage from the central nervous system (CNS) contribute to disease remains poorly described. In this project, we will investigate the consequences of compromised meningeal lymphatic function in TBI pathogenesis. In our preliminary studies, we found that TBI results in severely compromised brain lymphatic drainage and that pre-existing deficits in meningeal lymphatic function predisposes the brain to exacerbated clinical disease following brain trauma. To determine if the impaired clearance of endogenous damage/stress signals (e.g., cellular debris and necrotic cells) was associated with inflammatory signaling, we evaluated inflammasome complex formation in TBI. Inflammasomes are multiprotein oligomeric platforms that coordinate IL-1 and IL-18 production, as well as an inflammatory form of cell death in response to damage/stress signals. We find that injury-induced meningeal lymphatic dysfunction is associated with pronounced inflammasome formation and accumulation in the TBI brain. Moreover, our preliminary findings and work from others demonstrate critical roles for inflammasome activation in TBI disease pathogenesis. Given these collective findings, we hypothesize that aberrant inflammasome signaling that results from meningeal lymphatic dysfunction mechanistically contributes to TBI pathogenesis. To test this, we propose three aims. In Aim 1, we will employ a series of cutting-edge meningeal lymphatic modifying approaches to identify how modulation of brain drainage influences TBI disease progression. In Aim 2, will determine to what extent inflammasome signaling downstream of meningeal lymphatic dysfunction mechanistically contributes to TBI pathology. In the third Aim, we will investigate how CNS lymphatic decline that occurs with aging influences TBI disease outcomes in the elderly. This research is innovative because it will break new ground in our understanding of how disruptions in brain drainage and the resulting buildup of inflammasome oligomers influence CNS disease progression. Moreover, our preliminary studies suggest that modulation of the meningeal lymphatics and inflammasome signaling can potentially serve as much-needed therapeutic strategies to treat TBI, which further underscores the translational value of these studies.